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  • C07J—STEROIDS
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  • C07J1/0051—Estrane derivatives
  • C07J1/0066—Estrane derivatives substituted in position 17 beta not substituted in position 17 alfa
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  • C07J41/0072—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 the A ring of the steroid being aromatic

Definitions

• the present invention relates to novel compounds as pharmaceutical agents having in vitro a higher affinity for estrogen receptor preparations of rat prostate than for estrogen receptor preparations of rat uterus and in vivo a preferential effect on bone compared to uterus and / or pronounced effect for stimulating expression of 5HT2a Receptor and transporter, their preparation, their therapeutic application and pharmaceutical dosage forms containing the new compounds.
• the chemical compounds are novel steroidal tissue-selective estrogens.
• estrogens in the treatment of hormone-deficiency-related symptoms such as hot flashes, atrophy of estrogenic targets and incontinence, and the successful use of estrogen therapies to prevent bone loss in perimenopausal and postmenopausal women, are well documented and generally accepted (Grady et al , Ann Intern Med 117: 1016-1037). It is also well documented that estrogen replacement therapy in postmenopausal women or in women with differentiated ovarian dysfunction reduces the risk of cardiovascular disease over non-estrogen-treated women (Grady et al., Loc. Cit.).
• estrogen replacement therapy has been shown to be effective in reducing the incidence of colonic rectal cancer (Calle EF et al., 1995, J Natl Cancer Inst 87: 517-523).
• HRT estrogen or hormone replacement therapy
• natural estrogens such as estradiol and conjugated estrogens from horse urine are used either alone or in combination with a progestin.
• derivatives obtained by esterification e.g. 17 ⁇ -estradiol valerate.
• Endometriumkarzinomrisikos Harlap S 1992, Am J Obstet Gynecol 166: 1986-1992
• progestational component in the estrogen / progestogen combination avoids hypertrophy of the endometrium, however, the gestagen-containing combination is also associated with the occurrence of undesired intermenstrual bleeding.
• Selective estrogens are a newer alternative to the estrogen / progestogen combination preparations. To date, selective estrogens are understood to mean compounds which are estrogen-like on the brain, bone and vascular system but non-proliferative on the endometrium due to their anti-uterotrophic (i.e. antiestrogenic) partial action.
• SERMs selective estrogen receptor modulators
• Estrogen receptor beta (ER ⁇ ) Estrogen receptor beta
• ER ⁇ estrogen receptor ⁇
• the expression pattern of ER ⁇ differs from that of ER ⁇ (Kuiper et al., (1996) Endocrinology 138: 863-870).
• ER ⁇ predominates over ER ⁇ in the rat prostate, whereas in rat uterus ER ⁇ predominates over ER ⁇ .
• ER ⁇ is u.a. expressed in areas assigned importance for cognitive processes and 'mood' (Shugrue et al., 1997, J Comparative Neurology 388: 507-525).
• ER ⁇ in these glands could be the 5HT2a receptor and the serotonin transporters (Fink & B.E.H., Sumner 1996, Nature 383: 306, B.H.E., Sumner et al., 1999, Molecular Brain Research, in press).
• the neurotransmitter serotonin (5-hydroxytryptamine) is involved in the regulation of a variety of processes that may be compromised during menopause. In particular, the effects of menopause on mood and cognition are associated with the serotonergic system.
• Estrogen replacement therapy has been shown to be effective in treating these estrogen-deficiency-related symptoms, possibly by modulating serotonin receptor and transporter expression.
• ER ⁇ expression Other organ systems with relatively high levels of ER ⁇ expression include the bone (Onoe Y et al., 1997, Endocrinology 138: 4509-4512), the vasculature (TC registry, Adams MR 1998, J Steroid Molec Biol 64: 187-191), U.S. Pat Genitourinary tract (Kuiper GJM et al., 1997, Endocrinology 138: 863-870), the Gastrointestinal tract (Campbell-Thopson 1997, BBRC 240: 478-483) and the testis (Mosselmann S et al 1996 Febs Lett 392 49-53) including spermatids (Shugrue et al 1998, Steroids 63: 498-504).
• a selective estrogenic effect on specific target organs could be achieved due to the different tissue or organ distribution of the two subtypes of the ERs by subtype-specific ligands.
• Substances with a preference for ER ⁇ compared to ER ⁇ in the in vitro receptor binding assay were reported by Kuiper et al. (Kuiper et al., (1996) Endocrinology 138: 863-870).
• a selective effect of subtype-specific ligands of the estrogen receptor on estrogen-sensitive parameters in vivo has not previously been shown.
• the compounds are said to have a higher affinity for estrogen receptor preparations of rat prostates in vitro in estrogen receptor preparations of rat uterus and in vivo have a higher potency for protection against hormone deficiency-related bone mass loss compared to the uterine stimulating effect uterus and / or pronounced effect on stimulating the expression of 5HT2a receptor and transporter.
• US-A-3,806,546 describes 8 ⁇ -methyl-3-methoxy-estra-1,3,5 (10) -triene compounds having generic estrogenic activity.
• the present invention seeks to provide a structure-activity relationship that allows access to compounds that possess the pharmacological profile formulated above, better bone estrogenic activity than the uterus.
• ER- ⁇ selective active estrogens for the manufacture of a medicament for the treatment of the following estrogen-deficiency-related diseases and conditions,
• Substituents on the carbon atoms 6, 7, 11, 15, 16 and 17 may each be in the ⁇ - or ⁇ -position.
• 8 ⁇ -substituted estra-1,3,5 (10) -triene derivatives of the general formula I ⁇ are used, wherein R 6 ' , R 7' , R 9 , R 11 , R 14 , R 15 , R 15 ' and R 16 each represent a hydrogen atom or R 6' , R 7 ', R 14 , R 15 , R 15' and R 16 each represent a hydrogen atom and R 9 and R 11 together represent an additional bond and all other substituents have the meanings given in claim 1.
• estratriene derivatives of the general formula I When the estratriene derivatives of the general formula I 'contain further double bonds in the B, C and / or D ring, then preferably in the position 9 (11), 14 (15) or 15 (16) is a double bond or in positions 9 (11) and 14 (15) or 15 (16), two double bonds are present.
• estratriene derivatives of the general formula I ' wherein R 17 and R 17 'are a group R 18 -O- and a group R 18 -; a group R 18 - and a group -OC (O) R 22 , with R 18 and R 22 each in the meaning indicated under R 2 ; is.
• R 17 and R 17 ' is a hydroxy group and a hydrogen atom, a C 1 - C 4 alkyl or C 2 -C 4 alkenyl is and most preferably those wherein R 17 and R 17 'are a hydroxy group and a hydrogen atom, a methyl, ethynyl or prop-1-ynyl group is.
• R 16 ' is a group R 18 -O- or R 19 SO 2 -O- with R 18 and R 19 each in the meaning indicated under R 2 , R 17 and R 17 ' depending for is a hydrogen atom and all other substituents may have the meanings given in the general formula I '.
• Preferred according to the present invention is the use of one or more of the following compounds 8 ⁇ -methyl-estra-1,3,5 -tetraene-3,17 ⁇ -diol (10), 9 (11) 3-methoxy-8 ⁇ -methyl-estra-1,3,5 (10), 9 (11) -tetraen-17 ⁇ -ol 8 ⁇ -methyl-estra-1,3,5 (10) -triene-3,17 ⁇ -diol 3-methoxy-8 ⁇ -methyl-estra-1,3,5 (10) -trien-17 ⁇ -ol 8 ⁇ -vinyl-estra-1,3,5-tetraene-3,17 ⁇ -diol (10), 9 (11) 3-methoxy-8 ⁇ -vinyl-estra-1,3,5 (10), 9 (11) -tetraen-17 ⁇ -ol 8 ⁇ - (2 ', 2'-difluorovinyl) -estra-1,3,5 -tetraene-3,17 ⁇ -diol (11), 9 (11) 8 ⁇ - (2
• the invention also relates to the compounds of the general formula I themselves.
• R 3 is a group R 18 -O-, R 19 -SO 2 - Represents O- or OC (O) R 22 , where R 19 and R 22 are each as defined for R 2 , where R 18 is a hydrogen atom, a trifluoromethyl group, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, Neopentyl, heptyl, hexyl radical or an aryl, heteroaryl, or aralkyl radical may be and excluding the compounds of general formula I ', wherein R 3 is a hydroxy or acetyoxyl group, and simultaneously R 2 is a hydrogen atom, R 6 , R 6 ' , R 7 and R 7' each represent a hydrogen atom: R 8 is a hydrogen atom, R 6 , R 6 ' , R 7 and R 7' each represent a hydrogen
• Estratriene are usually described as intermediates, as estrogens in the conventional sense or for use in analytical methods.
• a halogen atom may always be a fluorine, chlorine, bromine or iodine atom; a fluorine atom is preferred.
• a chlorine atom is to be mentioned as a substituent.
• the hydrocarbon radicals which may be partially or fully halogenated, are fluorinated radicals.
• the hydrocarbon radical R 18 is, for example, a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, heptyl, hexyl radical.
• alkoxy groups OR 18 in the compounds of general formulas I and I ' may each contain 1 to 6 carbon atoms, with methoxy, ethoxy-propoxy-isopropoxy and t-butoxy groups being preferred.
• C 1 -C 5 -alkyl radicals R 20 and R 21 are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl.
• R 22 with 1 to max. 10 carbon atoms are, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, heptyl, hexyl and decyl mentioned; Methyl, ethyl, propyl and isopropyl are preferred.
• perfluorinated alkyl groups include trifluoromethyl, pentafluoroethyl and nonafluorobutyl.
• Representatives of the partially fluorinated alkyl groups include, for example, 2,2,2-trifluoroethyl, 5,5,5,4,4-pentafluoropentyl, 6,6,6,5,5,4,4,3,3-nonafluorohexyl, etc.
• C 3 -C 7 -cycloalkyl group is a cyclopropyl, butyl, pentyl, hexyl or heptyl group mentioned
• a C 4 -C 15 cycloalkylalkyl group has 3 to 7 carbon atoms in the cycloalkyl part; typical representatives are the cycloalkyl groups mentioned immediately above.
• the alkyl part has up to 8 carbon atoms.
• Examples of a C 4 -C 15 -cycloalkylalkyl radical are the cyclopropylmethyl, cyclopropylethyl, cyclopentylmethyl, cyclopentylpropyl, etc. may be mentioned.
• An aryl radical in the context of the present invention is a phenyl, 1- or 2-naphthyl radical; the phenyl radical is preferred.
• Aryl always also includes a heteroaryl radical.
• a heteroaryl radical are 2-, 3- or 4-pyridinyl, 2- or 3-furyl, 2- or 3-thienyl, 2- or 3-pyrrolyl, 2-, 4- or 5-imidazolyl, the pyrazinyl, the 2-, 4- or 5-pyrimidinyl or 3- or 4-pyridazinyl.
• substituents for an aryl or heteroaryl radical are methyl, ethyl, trifluoromethyl-pentafluoroethyl, trifluoromethylthio, methoxy, ethoxy, nitro, cyano, halogen (fluorine, chlorine, bromine, iodine), Hydroxy, amino, mono (C 1-8 alkyl) or di (C 1-8 alkyl) amino, where both alkyl groups are identical or different, di (aralkyl) amino, where both aralkyl groups are identical or different, mentioned.
• An aralkyl radical is a radical which contains up to 14, preferably 6 to 10, C atoms in the ring and 1 to 8, preferably 1 to 4, C atoms in the alkyl chain.
• suitable aralkyl radicals include benzyl, phenylethyl, naphthylmethyl, naphthylethyl, furylmethyl, thienylethyl, pyridylpropyl.
• the rings may be monosubstituted or polysubstituted by halogen, OH, O-alkyl, CO 2 H, CO 2 -alkoxy -NO 2 , -N 3 , -CN, C 1 -C 20 -alkyl, C 1 -C 20 - Acyl, C 1 -C 20 acyloxy groups.
• the alkyl groups or hydrocarbon radicals may be partially or fully fluorinated or substituted by 1-5 halogen atoms, hydroxy groups or C 1 -C 4 alkoxy groups.
• a C 2 -C 5 -alkenyl radical is meant primarily a vinyl or allyl radical.
• variants of the invention provide one or more, optionally conjugated Doppelbindurigen in the rings B, C and D of the estratriene skeleton before, namely one or more double bonds in the positions 6, 7; 9, 11; 11, 12; 14, 15 and 15, 16. Preference is given to a double bond in the position 11, 12th
• esters of the 8 ⁇ -substituted estratrienes according to the invention have advantages as prodrugs over the unesterified active compounds with respect to their mode of application, their mode of action, potency and duration of action.
• Steroids based on the 8 ⁇ -substituted estra-1,3,5 (10) triene scaffold are described in the present patent application for the treatment of estrogen receptor ⁇ -mediated diseases and conditions as selective estrogens, the in vitro dissociation for binding to Estrogen receptor preparations of rat prostate and rat uterus and in vivo preferably have a dissociation, for example, in terms of bone compared to uterine effect: over a wide dose range, these substances act bone-protective without stimulating the uterus.
• the substances in the male rat may have protective effect against orchiectomy-induced bone mass loss without inhibiting the secretion of the pituitary hormones LH and FSH. In the same dose range, their liver effect is low.
• the substances also exert estrogen-like effects on the vascular system and brain functions.
• Substances with higher binding to the rat prostate compared to the rat uterine estrogen receptor are more potent in increasing the expression of serotonin receptor and transporter, as compared to their positive effect on LH secretion. Therefore, processes in whose regulation the neurotransmitter serotonin is involved are favorably influenced, and the compounds of the present invention exert a favorable influence on mood and cognition, in particular.
• estrogens can be used as estrogens in the sense described in WO 97/45125 for the preparation of medicaments for influencing the levels of serotonin or of serotonin mRNA in humans.
• the 8 ⁇ -substituted estra-1,3,5 (10) trienes according to the invention are selective estrogens for the treatment of various conditions and diseases characterized by a higher content of estrogen receptor ⁇ than estrogen receptor ⁇ in the corresponding target tissue or organ , are suitable.
• the invention also relates to pharmaceutical preparations containing at least one compound of general formula I (or physiologically acceptable addition salts with organic and inorganic acids thereof) and the use of the compounds of general formula I 'for the preparation of medicaments, in particular for the following indications.
• the compounds both after oral and parenteral administration, can be used for the following indications.
• novel selective estrogens described in the present patent can be used as a single component in pharmaceutical preparations or in combination in particular with antiestrogens or gestagens. Particularly preferred is the combination of the selective estrogens with ER ⁇ selective antiestrogens, or with antiestrogens that are peripherally selectively active, i. who do not pass the blood-brain barrier.
• the substances and the pharmaceuticals containing them are particularly suitable for the treatment of peri- and post-menopausal symptoms, in particular hot flashes, insomnia, irritability, mood swings, incontinence, vaginal atrophy, hormone-deficiency-related mood disorders.
• the substances for hormone substitution and the therapy of hormone deficiency-related symptoms in surgical, drug or other conditional ovarian dysfunction are suitable. This includes prevention of bone loss in postmenopausal women and in andropausal men, in hysterectomized women or in women treated with LHRH agonists or antagonists.
• the compounds are also useful for alleviating the symptoms of andropause and menopause, i. for male and female hormone replacement therapy (HRT), for both prevention and treatment, and for the treatment of disorders associated with dysmenorrhea and for the treatment of acne.
• HRT hormone replacement therapy
• the substances are also useful for the prophylaxis of hormone deficiency-related bone mass loss and osteoporosis, for the prevention of cardiovascular diseases, in particular vascular diseases such as atherosclerosis, for the inhibition of the proliferation of arterial smooth muscle cells, for the treatment of primary pulmonary hypertension and for the prevention of hormone-deficiency-induced neurodegenerative diseases such as Alzheimer's disease, as well as hormone-deficiency-induced Impairment of memory and learning ability, can be used.
• cardiovascular diseases in particular vascular diseases such as atherosclerosis
• atherosclerosis for the inhibition of the proliferation of arterial smooth muscle cells
• hormone-deficiency-induced neurodegenerative diseases such as Alzheimer's disease, as well as hormone-deficiency-induced Impairment of memory and learning ability
• the substances are for the treatment of inflammatory and immune system disorders, in particular autoimmune diseases, such. Rheumatoid arthritis, can be used.
• the compounds can be used to treat male fertility disorders and prostatic diseases.
• the compounds may also be used in combination with the natural vitamin D3 or with calcitriol analogs for bone augmentation or as supportive therapy for therapies that cause bone mass loss (for example, glucocorticoid therapy, chemotherapy).
• the compounds of general formula I ' may be used in conjunction with progesterone receptor antagonists, particularly for use in hormone replacement therapy and for the treatment of gynecological disorders.
• the amount of a compound of general formula I 'to be administered will vary within a wide range and may cover any effective amount. Depending on the condition to be treated and the mode of administration, the amount of compound administered may be 0.01 ⁇ g / kg -10 mg / kg body weight, preferably 0.04 ⁇ g / kg -1 mg / kg body weight, per day. In humans, this corresponds to a dose of 0.8 ⁇ g to 800 mg, preferably 3.2 ⁇ g to 80 mg, daily.
• a dosage unit according to the invention contains 1.6 ⁇ g to 200 mg of one or more compounds of the general formula I '.
• the compounds according to the invention and the acid addition salts are suitable for the preparation of pharmaceutical compositions and preparations.
• the pharmaceutical compositions or medicaments contain as active ingredient one or more of the compounds according to the invention or their acid addition salts, optionally mixed with other pharmacologically or pharmaceutically active substances.
• the preparation of the drug is carried out in a known manner, wherein the known and customary pharmaceutical excipients and other conventional carriers and diluents can be used.
• excipients and auxiliaries are those which are recommended or indicated in the following references as adjuvants for pharmacy, cosmetics and adjacent areas: Ullmans Encyklopadie der ischen Chemie, Vol. 4 (1953), pages 1 to 39; Journal of Pharmaceutical Sciences, Vol. 52 (1963), page 918 et seq., H. v. Chr. Czetsch-Lindenwald, adjuvants for pharmacy and adjacent areas; Pharm. Ind., Issue 2, 1961, page 72 u. ff. H. P. Fiedler, Lexicon of excipients for pharmacy, cosmetics and adjacent areas, Cantor KG. Aulendorf in WORK 1971.
• the compounds may be administered orally or parenterally, for example, intraperitoneally, intramuscularly, subcutaneously or percutaneously.
• the compounds can also be implanted in the tissue.
• a pharmaceutically acceptable carrier such as, for example, starch, sugar, sorbitol, gelatin, lubricant, silicic acid, talc, etc.
• the active ingredients may be dissolved or suspended in a physiologically acceptable diluent.
• oils are often used with or without the addition of a solubilizer, surfactant, suspending or emulsifying agent. Examples of oils used are olive oil, peanut oil, cottonseed oil, soybean oil, castor oil and sesame oil.
• the compounds may also be used in the form of a depot injection or an implant preparation, which may be formulated to allow sustained release of active ingredient.
• Implants may contain as inert materials, for example, biodegradable polymers or synthetic silicones such as silicone rubber.
• the active ingredients can also be incorporated for percutaneous administration, for example in a plaster.
• the compounds may also be formulated as cyclodextrin clathrates.
• the compounds with ⁇ -, ⁇ - or ⁇ -cyclodextrin or derivatives of these are implemented (PCT / EP95 / 02656).
• the compounds of general formula I 'can also be encapsulated with liposomes.
• the substances described in the present patent have higher binding affinity to estrogen receptor from rat prostate than to estrogen receptor from rat uterus. It is assumed that ER ⁇ predominates over ER ⁇ in the rat prostate, and in rat uterus ER ⁇ over ER ⁇ . Table 1 shows that the ratio of prostate and uterine receptor binding is qualitatively consistent with the relative binding affinity (RBA) ratio of rat human ER ⁇ and ER ⁇ (according to Kuiper et al. (1996), Endocrinology 138: 863-870) ( Table 1).
• RBA relative binding affinity
• Table 1 shows that the ratio of prostate and uterine receptor binding is qualitatively consistent with the relative binding affinity (RBA) ratio of rat human ER ⁇ and ER ⁇ (according to Kuiper et al. (1996), Endocrinology 138: 863-870) ( Table 1).
• RBA relative binding affinity
• Table 2 shows the results for the compound 8 ⁇ -methyl-estra-1,3,5 (10) -triene-3,17 ⁇ -diol to be used according to the invention (compound D) as well as for the compounds according to the invention 8 ⁇ -Vinyl-estra-1,3,5 (10), 9 (11) -tetraene-3,17 ⁇ -diol (A) 8 ⁇ -vinyl-estra-1,3,5 (10) -triene-3,17 ⁇ -diol (B) 8 ⁇ - (2,2-difluorovinyl) -estra-1,3,5 (10) -triene-3,17 ⁇ -diol (C) and 8 ⁇ -ethyl-estra-1,3,5 (10) -triene-3,17 ⁇ -diol (E).
• the compounds A, B, C, D and E show a higher binding affinity to the estrogen receptor from rat prostate than to the estrogen receptor from rat uterus.
• Prostate ER preferential substances are preferably dissociated in vivo for bone and uterine effect in favor of bone action.
• Substances with higher binding to the rat prostate compared to the rat uterine estrogen receptor are also more potent in increasing the expression of serotonin receptor and transporter, as compared to their positive effect on LH secretion.
• 3-month-old female rats are ovariectomized and treated with the test compound once a day for 28 days immediately after surgery.
• the application is subcutaneous in arachis oil / ethanol.
• the animals are killed the day after the last application and tibia and uteri are removed.
• the uteri are weighed, fixed and processed for histological examinations.
• Bone density is determined ex vivo on prepared long bones by means of pQCT (Quantitative Computed Tomography). Measurements are taken 4-6 mm from the proximal tibial condyle.
• the ovariectomy reduces the density of the trabecular bone in the measured range from about 400 mg Ca 2+ / cm 3 to about 300 mg Ca 2+ / cm 3 .
• the higher binding affinity for estrogen receptor from rat prostate than for estrogen receptor from rat uterus is preferably reflected in significantly lower levels of the compounds of the present invention which provide 50% bone protection as compared to the 50% uterine stimulation induced amounts Bone mass loss that is measurable in ovariectomized, untreated female rats 28 days after ovariectomy, in contrast to sham-punctured, intact animals.
• the vascular effect of the estrogens according to the invention is determined in the model of the ApoE knockout mouse, as described by R. Elhage et al., 1997, and in the model of balloon catheter-induced vascular injury (restenosis model) (Elhage R. et al., 1997, Arteriosclerosis, Thrombosis , and Vascular Biology 17: 2679-2684).
• oxytocin, oxytocin receptor or vasopressin mRNA expression is used as a surrogate parameter (Hrabovszky E et al., 1998, Endocrinology 1339: 2600-2604).
• OvariektomATOR rats are treated for 7 days with the test substance or vehicle (application: subcutaneously or orally, 6 times a day).
• the animals are decapitated, the uterine weight is determined and the oxytocin, oxytocin receptor or vasopressin mRNA level is examined by in situ hybridization on appropriate brain slices.
• the ED 50 values for stimulating uterine growth and induction of oxytocin receptor mRNA are determined.
• Another possibility for detecting the dissociated estrogen effect of the substances according to the invention in vivo is, after single application of the substances in rats, measuring effects on the expression of 5HT2a receptor and serotonin transporter protein and mRNA levels in ER ⁇ -rich gum areas. Compared to the effect on serotonin receptor and transporter expression, the effect on LH secretion is measured. Substances with higher binding to the rat prostate compared to the rat uterine estrogen receptor are more potent in increasing the expression of serotonin receptor and transporter compared to their positive effect on LH secretion. The density of serotonin receptor and transporter is determined on brain sections by means of radioactive ligands, the corresponding mRNA by means of in situ hybridization. The method is described in the literature: G. Fink & B.E.H. Sumner 1996 Nature 383: 306; E.H. Sumner et al. 1999 Molecular Brain Research, in press.
• substances A, B, C, D, and E of the present invention result in increased expression of the serotonin receptor and transporter.
• Etherification and / or esterification of free hydroxy groups takes place by methods familiar to the person skilled in the art.
• the compounds of the invention may be present at the carbon atoms 6, 7, 11, 15, 16 and 17 as ⁇ , ⁇ -stereoisomers.
• the compounds In the preparation of the compounds according to the described methods, the compounds usually fall as mixtures of the corresponding ⁇ , ⁇ -isomers. The mixtures can be separated, for example, by chromatographic methods.
• Substituents which are possible according to the general formula I may already be present in the starting form or in the form of a precursor in the starting product, an estron already corresponding to the desired end product.
• 17-Substituents are, also by known methods, introduced by nucleophilic addition of the desired substituent or a reactive precursor thereof, and optionally further developed.
• the 8 ⁇ -substituted estratriene carboxylic acid esters according to the invention are prepared analogously to likewise known processes from the corresponding hydroxysteroids (see, for example, Pharmaceutical Active Ingredients, Syntheses, Patents, Applications, A. Kleemann, J. Engel, Georg Thieme Verlag, Stuttgart 1978. Arzneistoff, Fort Kunststoff 1972 to 1985, A. Kleemann, E. Lindner, J. Engel (ed.), 1987 VCH, pages 773-814).
• estratriene sulfamates according to the invention are obtainable in a manner known per se from the corresponding hydroxy steroids by esterification with sulfamoyl chlorides in the presence of a base (Z. Chem., 15, 270-272 (1975); Steroids 61, 710-717 (1996)).
• Subsequent acylation of the sulfamide group leads to the (N-acyl) sulfamates according to the invention, for which pharmacokinetic advantages have already been demonstrated in the absence of an 8-substituent (compare DE 195 40 233 A1).
• the preparation of the sulfamates according to the invention with one or more additional hydroxyl groups in the molecule is also possible by starting from suitable hydroxy-steroid ketones. First, depending on the objective, one or more hydroxyl groups are subjected to sulfamoylation. Then the sulfamate groups can optionally be converted with a desired acyl chloride in the presence of a base in the respective / N-acyl) sulfamates. The now present oxosulfamates or oxo (N-acyl) sulfamates are converted by reduction into the corresponding hydroxysulfamates or hydroxy- (N-acyl) sulfamates (Steroids 61, 710-717 (1996)). Suitable reducing agents are sodium borohydride and the borane-dimethyl sulfide complex.
• Functionalizations at the carbon atom 2 are possible, for example, by electrophilic substitution after prior deprotonation of position 2 of the corresponding 3- (2-tetrahydropyranyl) or 3-methyl ether with a lithium base (eg methyllithium, butyllithium).
• a fluorine atom may be introduced by reacting the C-H activated substrate with a fluorination reagent such as N-fluoromethanesulfonimide (WO 94/24098).
• variable substituents in the rings B, C and D of Estratriengerüstes can in principle be carried out according to the chemical teaching known to those skilled in the corresponding, in the 8-position unsubstituted Estratrienderivate be prepared (see, inter alia: steroids, LF Fieser, M Fieser, Verlag Chemie, Weinheim / Bergstr., 1961; Organic Reactions in Steroid Chemistry, J. Fried, JA Edwards, Van Nostrand Reinhold Company, New York, Cincinnati, Toronto, London, Melbourne, 1972; Medicinal Chemistry of Steroids, FJ Zeelen, Elsevier, Amsterdam, Oxford, New York, Tokyo, 1990). That concerns for example, the introduction of substituents such as hydroxyl or alkoxy groups, alkyl, alkenyl or alkynyl groups or halogen, in particular fluorine.
• substituents according to the general formula I can also be introduced at the stage of the estratrienes already substituted in the 8-position. This can be useful or necessary in particular in the case of multiple substitution of the desired end compound.
• the starting material for such syntheses are 11-keto-estratetraene derivatives of types 1 and 2 (US Pat. No. 3,491,089, Tetrahedron Letters, 1967, 37, 3603), which are substituted stereoselectively in position 8 ⁇ in the reaction with diethylaluminum cyanide.
• Subsequent reduction of the carbonyl function on C (11) and elimination of the resulting hydroxyl group leads to the formation of 8 ⁇ -substituted estra-1,3,5 (10), 9 (11) tetraenes, which in turn can be converted into 8 ⁇ -aldehydes.
• Functionalization for example by Wittig reactions with subsequent removal of the protective groups, leads to the 8 ⁇ -sterols according to the invention.
• the 11-oxygenated estradiol derivatives initially obtained in this sequence, as well as the double bond C (9) -C (11), can be further converted to a variety of substitution patterns on the steroid by methods known to those skilled in the art.
• an 11 ⁇ -hydroxy group can be prepared by the method described by Vorbrüggen et al. be converted into a 11 ⁇ -fluorine atom.
• the following synthetic strategy is used in particular.
• the 8 ⁇ -carbonyl function is protected as acetal.
• the 17-ketosteroid can be converted into a sulfonylhydrazone, in the simplest case by reaction with Phenylsulfonyl hydrazide.
• Phenylsulfonyl hydrazide By a degradation reaction, the formation of C (16) -C (17) olefin (Z. Chem. 1970, 10, 221-2, Liebigs Ann. Chem.
• reaction solution was poured into ice-water, extracted several times with ethyl acetate, the collected organic phases with sat. Washed with sodium chloride solution, dried over magnesium sulfate and i. Vak. concentrated. The dark, oily crude product (330 mg) was used without further purification in the next step.
• the oily crude product of the last stage was dissolved in 10 ml of methanol, treated with 1 ml of water and 250 mg of oxalic acid dihydrate and heated to 60 ° C for 1 h.
• For workup was diluted with ethyl acetate, successively with sat. Sodium bicarbonate solution and sat. Washed with sodium chloride solution, dried over magnesium sulfate and i. Vak. concentrated.
• the resulting 2-fluoro-8 ⁇ -vinyl-estra-1,3,5 (10) triene-3,17 ⁇ -diol (15 mg, 18%) had a mp of 67-73 ° C.
• the oily product of the ietzien stage was dissolved in 3 ml of methanol, treated with 0.3 ml of water and 50 mg of oxalic acid dihydrate and heated to 60 ° C for 1 h.
• For workup was diluted with ethyl acetate, successively with sat. Sodium bicarbonate solution and sat. Washed with sodium chloride solution, dried over magnesium sulfate and i. Vak. concentrated.
• the resulting yellowish, powdery 8 ⁇ -vinyl-estra-1,3,5 (10) -triene-2,3,17 ⁇ -triol had a mp of 82-85 ° C (Zers. ) on.

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